This invention relates to crystalline N-[4-[[(2-amino-1,4,5,6,7,8-hexahydro-4-oxo-(6S)- and -(6R)-pteridinyl)methyl]amino]benzoyl]-Lglutamic acid (termed crystalline (6S)- or (6R)-tetrahydrofolic acid herein-below), to its use, and to a process for its preparation.
Tetrahydrofolic acid derivatives have 2 asymmetric centres. Since these derivatives are synthesized from folic acid, i.e. N-(pteroyl)-L-glutamic acid, the optically active C atom in the glutamic acid moiety is in the L form, while the optically active C atom in the 6-position, which is usually formed by hydrogenation of the double bond in the 5,6-position of the pteroyl radical, exists in the racemic, i.e. (6R,S) form. Accordingly, synthetic tetrahydrofolic acid derivatives are composed of a 1:1 mixture of 2 diastereomers.
Tetrahydrofolates are mainly used in the form of calcium 5-formyl-5,6,7,8-tetrahydrofolate (leucovorin) or calcium 5-methyl-5,6,7,8-tetrahydrofolate as pharmaceuticals for the treatment of megaloblastic folic acid anaemia, as an antidote for improving the tolerance of folic acid antagonists, specifically aminopterin and methotrexate in cancer therapy ("antifolate rescue"), for enhancing the therapeutic effect of fluorinated pyrimidines and for the treatment of autoimmune diseases such as psoriasis and rheumatic arthritis, for improving the tolerance of certain antiparasitics, such as trimethoprim-sulfamethoxazole, and for reducing the toxicity of dideazatetrahydrofolates in chemotherapy. Tetrahydrofolic acid is also used as starting material for the preparation of a variety of tetrahydrofolic acid derivatives.
To date, the direct use of tetrahydrofolic acid as a pharmaceutical and as a starting material for the preparation of a variety of tetrahydrofolic acid derivatives was made impossible for all practical purposes by the difficulty encountered when preparing tetrahydrofolic acid in a purity which is acceptable for a pharmaceutical active substance and by the extreme instability of tetrahydrofolic acid, in particular its pronounced sensitivity to oxidation [see, in this context, also A. L. Fitzhugh, Pteridines 4(4), 187-191 (1993)]. Various methods were developed to overcome this instability, and particular mention must be made in connection with the present invention of DE-OS 2 323 124. Specific mention must also be made of EP 600 460 corresponding to U.S. Pat. No. 5,489,684 in the context of processes for the preparation of tetrahydrofolic acid an in connection with the present invention. However, no process which is feasible on an industrial scale has been found to date for the preparation of ultrapure, sufficiently stable tetrahydrofolic acid which would allow the pharmaceutical application of tetrahydrofolic acid.